Schistosomiasis is a worldwide parasitic disease caused by blood flukes of the Schistosoma genus. In preliminary studies to this revised application, we investigated the major immune response to parasite-derived antigens in rodents and primates infected with S. mansoni, S. japonicum and S. haematobium. Our results show that schistosome infection induces significant 1gM, IgG, IgA and IgE responses to at least 5 major glycan-based (carbohydrate-based) antigens on worm-derived soluble and membrane glycoproteins. These antigenic glycans occur in di- and trisaccharide sequences containing fucose, galactose, xylose, N-acetylglucosamine and N-acetylgalactosamine. The major antigens we have identified are designated the Lewis x (Lex), lacdiNAc (LDN), fucosylated LDN (LDNF), core-Xylose and coreFucose. We hypothesize that specific anti-glycan antibodies in schistosome-infected animals may provide protective immunity against the parasite. We will directly test this hypothesis and develop more information about immunity to schistosome glycans in 4 specific aims. (Aim 1) We will synthesize a panel of novel schistosome glycan epitopes and conjugate them to protein carriers to test their recognition by sera from infected animals. (Aim 2) We will use available monoclonal antibodies (mAbs) and others to be obtained to develop new diagnostic immunoassays to detect the presence of circulating schistosome glycoconjugates and antibodies to these glycoconjugates. With these reagents we will explore the immunity developed toward schistosome glycoconjugates upon infection with different numbers of cercariae and further define the expression and localization of schistosome glycan antigens during development. (Aim 3) We will test the protective effects of Abs to specific glycans by passive transfer experiments with mAbs, affinity purified anti-glycan Abs from sera of infected animals, and antisera depleted of specific anti-glycan Abs by absorption to defined glycans. (Aim 4) We will immunize mice with specific glycan conjugates and evaluate the in vivo protective capacity of glycan conjugates upon cercarial challenge and also by passive transfer experiments. These planned experiments will give new information about the fundamental nature of immunity to glycan antigens in schistosome-infected animals and provide a critical assessment of the hypothesis regarding the possible protective immunity elicited by anti-glycan responses.